Submissions for variant NM_001317778.2(SFTPC):c.523C>G (p.Leu175Val)

gnomAD frequency: 0.00042  dbSNP: rs201685063

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000262185	SCV000473027	likely benign	Interstitial lung disease 2	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000331564	SCV000473028	likely benign	Surfactant metabolism dysfunction, pulmonary, 2	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Johns Hopkins Genomics, Johns Hopkins University	RCV000331564	SCV001425401	uncertain significance	Surfactant metabolism dysfunction, pulmonary, 2	2020-04-10	criteria provided, single submitter	clinical testing	This variant has been previously reported in individuals with pulmonary disease of varying severity. SFTPC c.541C>G (rs201685063) is present in a large population dataset (gnomAD: 147/280168 total alleles; 0.052%%; no homozygotes). A single submitters in ClinVar classifies this variant as likely benign. This variant is located within an important domain of the COOH flanking propeptide. Three bioinformatic tools queried predict that the substitution would be damaging, but these algorithms have low specificity, especially for predicting gain of function or dominant negative variants. Due to insufficient evidence, we consider the clinical significance of c.541C>G to be uncertain at this time.
Invitae	RCV001431879	SCV001634641	likely benign	not provided	2023-05-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002348113	SCV002654004	uncertain significance	Hereditary pulmonary alveolar proteinosis	2017-07-18	criteria provided, single submitter	clinical testing	The p.L181V variant (also known as c.541C>G), located in coding exon 5 of the SFTPC gene, results from a C to G substitution at nucleotide position 541. The leucine at codon 181 is replaced by valine, an amino acid with highly similar properties. This variant was first described in a child with interstitial lung disease (ILD), whose asymptomatic mother was found to carry the same mutation (McBee AD et al. Pediatr. Pulmonol., 2008 May;43:443-50). This variant was further described in one sporadic and one familial case of ILD; however, information on familial members and clinical symptoms was not provided. The familial case of ILD also carried a second alteration in SFTPC (Willander H et al. Proc. Natl. Acad. Sci. U.S.A., 2012 Feb;109:2325-9). A one-year-old child with irregular lung anatomy and a family history of pulmonary fibrosis was also observed to have this variant; however there was no information on familial segregation of this alteartion (Soares JJ et al. Pediatrics, 2013 Oct;132:684-91). This variant was identified in cis with another SFTPC alteration in an infant with tachydyspnea, respiratory infections, chronic cough, hypoxia retractions, and failure to thrive; both alterations were also identified in the infant's father who has a history of recurrent otitis media (Kröner C et al. Eur. Respir. J., 2015 Jul;46:197-206). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear.
GeneDx	RCV001431879	SCV003852926	uncertain significance	not provided	2023-03-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25657025, 24081995, 22308375, 36622818, 18383112)
Revvity Omics, Revvity	RCV000331564	SCV004237875	likely benign	Surfactant metabolism dysfunction, pulmonary, 2	2023-11-16	criteria provided, single submitter	clinical testing