Submissions for variant NM_152393.4(KLHL40):c.1273G>A (p.Gly425Ser)

gnomAD frequency: 0.00081  dbSNP: rs138791086

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001087824	SCV000654235	likely benign	Nemaline myopathy 8	2025-01-25	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000536469	SCV001144387	likely benign	not provided	2019-02-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001087824	SCV001522103	uncertain significance	Nemaline myopathy 8	2019-08-03	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV000536469	SCV001811132	likely benign	not provided	2019-12-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002526698	SCV003701725	uncertain significance	Inborn genetic diseases	2021-07-14	criteria provided, single submitter	clinical testing	The c.1273G>A (p.G425S) alteration is located in exon 2 (coding exon 2) of the KLHL40 gene. This alteration results from a G to A substitution at nucleotide position 1273, causing the glycine (G) at amino acid position 425 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV001087824	SCV003810072	likely benign	Nemaline myopathy 8	2023-06-12	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000536469	SCV001553369	likely benign	not provided		no assertion criteria provided	clinical testing	The KLHL40 p.Gly425Ser variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs138791086) and ClinVar (classified as uncertian significance by Invitae). The variant was identified in control databases in 271 of 282578 chromosomes (1 homozygous) at a frequency of 0.000959 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 14 of 7224 chromosomes (freq: 0.001938), Latino in 52 of 35432 chromosomes (freq: 0.001468), European (non-Finnish) in 182 of 128968 chromosomes (freq: 0.001411), East Asian in 8 of 19944 chromosomes (freq: 0.000401), African in 8 of 24916 chromosomes (freq: 0.000321), European (Finnish) in 4 of 25116 chromosomes (freq: 0.000159) and South Asian in 3 of 30616 chromosomes (freq: 0.000098), but was not observed in the Ashkenazi Jewish population. The p.Gly425 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.