Submissions for variant NM_000587.4(C7):c.405del (p.Asn136fs)

gnomAD frequency: 0.00088  dbSNP: rs139491301

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498123	SCV000590520	likely pathogenic	not provided	2017-06-19	criteria provided, single submitter	clinical testing	The c.405delT variant in the C7 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.405delT variant causes a frameshift starting with codon Asparagine 136, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Asn136ThrfsX2. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.405delT variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.405delT as a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000498123	SCV002234370	pathogenic	not provided	2024-10-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn136Thrfs*2) in the C7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in C7 are known to be pathogenic (PMID: 9856499, 17407100). This variant is present in population databases (rs139491301, gnomAD 0.3%). This premature translational stop signal has been observed in individual(s) with terminal pathway complement deficiency (PMID: 31440263). ClinVar contains an entry for this variant (Variation ID: 432759). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002489221	SCV002781829	likely pathogenic	Complement component 7 deficiency	2022-04-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003419845	SCV004115152	pathogenic	C7-related disorder	2022-08-29	criteria provided, single submitter	clinical testing	The C7 c.405delT variant is predicted to result in a frameshift and premature protein termination (p.Asn136Thrfs*2). This variant has been reported in the homozygous state in multiple individuals with Complement C7 deficiency (El Sissy et al 2019. PubMed ID: 31440263; Rosain J et al 2017. PubMed ID: 28368462). This variant is reported in 0.28% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-40936563-CT-C). Frameshift variants in C7 are expected to be pathogenic. This variant is interpreted as pathogenic.